Highly concentrated stable meloxicam solutions

ABSTRACT

Aqueous cyclodextrin-free solution of meloxicam for administration by oral or parenteral route, containing a pharmacologically acceptable meloxicam salt of an organic or inorganic base and one or more suitable excipients, the content of dissolved meloxicam salt being more than 10 mg/mL. The formulation according to the invention has a shelf-life of up to 24 months or more.

[0001] The present invention relates to highly concentrated stablemeloxicam solutions for oral and parenteral administration, particularlyfor treating respiratory diseases in large farm animals.

BACKGROUND OF THE INVENTION

[0002] Meloxicam(4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide) is an active substance which belongs to the group ofNSAIDs (non-steroidal antiinflammatory drugs). Meloxicam and the sodiumand meglumine (N-methyl-D-glucamine) salt thereof are described inEP-A-0 002 482. EP-A-0 002 482 shows, inter alia, the example of a 0.2%injectable solution of meloxicam consisting of the meglumine salt of theactive substance, sodium chloride, and water.

[0003] EP-A-0 945 134 discloses the pH-dependent solubilitycharacteristics of meloxicam and its salts, i.e., the sodium salt, theammonium salt, and the meglumine salt, in aqueous solution. According toEP-A-0 945 134, meloxicam is an active substance which does not dissolvereadily in water and the meloxicam salts, particularly the megluminesalt, exhibit improved solubility as the pH increases between 4 and 10,as shown in Table 1 of EP-0 945 134. However, until now it has only beenpossible to produce stable, clear, aqueous solutions with a lowconcentration of meloxicam. In addition to involving the in situformation of a meloxicam salt, e.g., meglumine salt, and the addition ofsolubilizers, these prior art solutions were required to have a pH inthe range of maximum possible solubility as well as being reasonablywell-tolerated and contain a high proportion of organic solvent.Formulation tests with the same or a similar recipe led to cloudiness ofthe solution if the meloxicam concentrations were higher, e.g., 2%.

[0004] WO9959634 A1 describes an eye drop solution containing 0.5%meloxicam but makes no reference to possible meloxicam concentrationsover 1%. For example, a commercially available 0.5% meloxicam solutionis used in small animals such as dogs, heifers, and calves to treatrespiratory diseases.

[0005] Thus, it has not hitherto been possible to treat large farmanimals with an injectable meloxicam solution as the low concentrationof active substance in the injectable solution did not allow anacceptable, well-tolerated injection volume due to the great weight ofthe animals. Furthermore, parenteral administration requires that thesolution be free from particles; if there are particles in a parenteraldrug, there is a risk of vascular damage or embolism. Moreover, organicsolvents, solubilizers, and water-soluble substances can only be used incertain concentrations to achieve acceptable drug tolerance. Theseproblems are solved by the present invention which providesparticle-free, highly concentrated meloxicam solutions which are stableover long periods and suitable for treating farm animals up to 750 kg inweight. The meloxicam solutions of the present invention should,therefore, be suitable for administration both orally or parenterally.

DESCRIPTION OF THE INVENTION

[0006] Surprisingly, it has been found that highly concentratedmeloxicam solutions which contain, in addition to a meloxicam salt andcertain excipients, another excipient selected from among citric acid,lecithin, gluconic acid, tartaric acid, phosphoric acid, and EDTA or thesalts thereof, may be produced so as to be particle-free and stable overlong periods. The stability was achieved with an unexpectedly smallamount of organic solubilizers. The formulation was found to be stableeven when subjected to the process of final sterilization.

[0007] This results in the solution to the problem according to theinvention, as a formulation of a meloxicam solution which contains, inaddition to a meloxicam salt, small concentrations of solubilizer, apreservative, a buffer substance for achieving the optimum pH range, andanother excipient.

[0008] The invention relates to aqueous cyclodextrin-free solutions ofmeloxicam for parenteral or oral administration which contain apharmacologically acceptable meloxicam salt of an organic or inorganicbase in a highly concentrated solution with 11-25 mg/mL of meloxicamtogether with suitable excipients.

[0009] The formulation according to the invention overcomes the problemarising from the prior art of providing an injectable solution of theactive substance meloxicam which is also suitable for treating largefarm animals, by permitting a high concentration of active substance ina particle free solution which is stable over the long term, having thecomposition described hereinafter.

[0010] The formulation according to the invention may contain, as themeloxicam salt, the meglumine, sodium, potassium, or ammonium salt,preferably the meloxicam meglumine salt.

[0011] The solubilizers used may be, for example, polyethyleneglycols,polyoxyethylene-polyoxypropylene copolymers (e.g., Poloxamer 188),glycofurol, arginine, lysine, castor oil, propyleneglycol, solketal,polysorbate, glycerol, sorbitol, mannitol, xylitol,polyvinylpyrrolidone, lecithin, cholesterol, 12-hydroxystearicacid-PEG660-ester, propyleneglycol monostearate, polyoxy-40-hydrogenatedcastor oil, polyoxyl-10-oleyl-ether, polyoxyl-20-cetostearylether, andpolyoxyl-40-stearate or a mixture of sorbitol, mannitol and xylitol,preferably polyethyleneglycols, polyoxyethylene-polyoxypropylenecopolymers, glycofurol, polyvinylpyrrolidone, lecithin, cholesterol,12-hydroxystearic acid-PEG660-esters, propyleneglycol monostearate,polyoxy-40-hydrogenated castor oil, polyoxyl-10-oleyl-ether,polyoxyl-20-cetostearylether, and polyoxyl-40-stearate. Particularlypreferred are polyethyleneglycols, glycofurol, andpolyoxyethylene-polyoxypropylene-copolymers, but especiallypolyethyleneglycols (e.g., Macrogol 300) andpolyoxyethylene-polyoxypropylene copolymers (e.g., Poloxamer 188). Thepreservatives used may be, for example, ethanol, benzoic acid and thesodium or potassium salts thereof, sorbic acid and the sodium orpotassium salts thereof, chlorobutanol, benzyl alcohol, phenylethanol,the methyl, ethyl, propyl, or butyl p-hydroxybenzoates, phenol,m-cresol, p-chloro-m-cresol, or benzalkonium chloride. Particularlypreferred are ethanol, benzoic acid and the sodium or potassium saltsthereof, sorbic acid and the sodium or potassium salts thereof,chlorobutanol, benzyl alcohol, phenylethanol, and the methyl, ethyl,propyl, or butyl p-hydroxybenzoates, but preferably ethanol, benzoicacid and the sodium or potassium salts thereof, sorbic acid and thesodium or potassium salts thereof, but especially ethanol.

[0012] The buffer system used to achieve a pH of between 8 and 10 maybe, for example, glycine, a mixture of glycine and HCl, a mixture ofglycine and sodium hydroxide solution, and the sodium and potassiumsalts thereof, a mixture of potassium hydrogen phthalate andhydrochloric acid, a mixture of potassium hydrogen phthalate and sodiumhydroxide solution, or a mixture of glutamic acid and glutamate.Glycine, a mixture of glycine and HCl, and a mixture of glycine/sodiumhydroxide solution, especially glycine, are particularly preferred.

[0013] Other suitable excipients are citric acid, lecithin, gluconicacid, tartaric acid, phosphoric acid, and EDTA or the alkali metal saltsthereof, preferably tartaric acid and EDTA or the alkali metal saltsthereof, particularly disodium EDTA.

[0014] One embodiment of the invention contains, in addition to themeglumine or sodium salt of meloxicam, polyethyleneglycols, glycofuroland/or polyoxyethylene-polyoxypropylene copolymers, but particularlypolyethyleneglycols (e.g., Macrogol 300) and/orpolyoxyethylene-polyoxypropylene copolymers (e.g., Poloxamer 188) assolubilizer, ethanol, benzoic acid and the sodium or potassium saltsthereof, or sorbic acid and the sodium or potassium salts thereof, butparticularly ethanol, as preservative, and glycine, a mixture ofglycine/HCl, or a mixture of glycine/sodium hydroxide solution, butpreferably glycine, as buffer, and disodium EDTA as an additionalexcipient.

[0015] The formulation according to the invention may contain meloxicamin a concentration of 11-25 mg/mL, preferably 13-24 mg/mL, preferably16-23 mg/mL, particularly preferably 18-22 mg/mL, and especially 20mg/mL.

[0016] The meglumine concentration may be between 12.5 and 16.5 mg/mL,preferably 13-16 mg/mL, preferably 13.5-15.5 mg/mL, more preferably14-15 mg/mL, and especially about 14 mg/mL. The possible sodium,potassium, and ammonium concentrations are calculated accordingly.

[0017] The concentration of the solubilizers may be in the range from20-200 mg/mL, preferably 30-150 mg/mL, preferably 40-130 mg/mL, morepreferably 50-120 mg/mL, and especially 70-100 mg/mL.

[0018] The concentration of the preservative ethanol may be in the rangefrom 100-200 mg/mL, preferably 120-180 mg/mL, and more preferably about150 mg/mL.

[0019] The concentration of the preservatives benzoic acid and thesodium or potassium salts thereof, sorbic acid and the sodium orpotassium salts thereof, chlorobutanol, benzyl alcohol, phenylethanol,phenol, m-cresol, and p-chloro-m-cresol, may be in the range from 0.5-50mg/mL, preferably 1-10 mg/mL, and more preferably 3-5 mg/mL.

[0020] The concentration of the preservatives benzalkonium chloride,phenylmercury nitrate, and methyl, ethyl, propyl, orbutyl-p-hydroxybenzoates, may be in the range from 0.01-4 mg/mL,preferably 0.02-3 mg/mL, and more preferably 0.1-0.5 mg/mL.

[0021] The concentration of the buffer substances may be between 4 and50 mg/mL, preferably between 5 and 20 mg/mL, and more preferably between8 and 10 mg/mL.

[0022] The concentration of the other excipients mentioned above, e.g.,EDTA, citric acid, lecithin, gluconic acid, tartaric acid, andphosphoric acid or the salts thereof, may be in the range from 0.2-3mg/mL, preferably 0.3-2.5 mg/mL, preferably 0.5-2 mg/mL, most preferably0.6-1.5 mg/mL, and in particular 0.7-1.0 mg/mL.

[0023] Meglumine and meloxicam may be used in a molar ratio of between9:8 and 12:8, preferably in a molar ratio of 11:8, but especially in amolar ratio of 10:8.

[0024] In the formulation according to the invention, meloxicam and theother excipient, particularly disodium EDTA, may be present in a weightratio of between 25:1 and 15:1, preferably between 24:1 and 16:1,preferably between 23:1 and 17:1, more preferably between 22:1 and 18:1,most preferably between 21:1 and 19:1, and in particular about 20:1.

[0025] The formulation according to the invention may have shelf-lifeafter opening of 28 days or more.

[0026] The shelf-life of the solution in the sealed original packagingmay be 1 month or more, in particular between 1 month and 24 months, butat least between 1 month and 18 months, preferably between 1 month and12 months, more preferably between 1 month and 9 months, most preferablybetween 1 month and 6 months, particularly between 1 month and 3 months.Details of the stability tests by way of example can be found in TablesI and 2 which follow:

[0027] Test of Stability After Opening

[0028] Packing material: 50 mL colorless glass vials, glass type I,ethylenepropylenenorbornene terpolymer rubber stopper (Type: WI 640grey), aluminium flanged cap.

[0029] Recipe: analogous to Example 1 of the description

[0030] 4 mL samples were taken from the storage samples three times aday for six days and on the seventh day 4 mL samples were taken fourtimes. Storage was then continued until 28 days had elapsed and sampleswere taken again. TABLE 1 Test Storage conditions Storage time Meloxicamcontent No. [° C./% relative humidity] [Days] [mg/mL] 1 25° C. 0 19.725° C./60% 28 19.2 2 25° C. 0 20 25° C./60% 28 19.2

[0031] In both samples, in addition to the meloxicam content, theparameters investigated, namely appearance (clear yellow solution), pH(8.0-9.7), ethanol content (13.5-15.75), disodium EDTA content(85.0-110.0 mg/100 mL), sterility (according to Pharm. Eur. and USP),and the stability of the packaging material were found to be unchanged.

[0032] Long Term Stability Test in Sealed Original Packaging

[0033] Packaging material: 50 mL colorless glass vials, glass type I,ethylenepropylenenorbornene terpolymer rubber stopper (Type: WI 640grey), aluminium flanged cap.

[0034] Recipe: Analogous to Example 1 of the Description TABLE 2 TestStorage conditions Storage time Meloxicam content No. [° C./% relativehumidity] [Days] [mg/mL] 1 25° C. 0 19.7 4° C. 6 19.9 40° C./75% 6 19.525° C./60% 18 19.3 30° C./70% 18 19.4 2 25° C. 0 20.0 4° C. 6 19.9 40°C./75% 6 19.7 25° C./60% 18 19.4 30° C./70% 18 19.5 25° C./60% 24 19.530° C./70% 24 19.5

[0035] In both samples, in addition to the meloxicam content, theparameters investigated, namely appearance (clear yellow solution), pH(8.0-9.7), ethanol content (13.5-15.75), disodium EDTA content(85.0-110.0 mg/100 mL), sterility (according to Pharm. Eur. and USP),and the stability of the packaging material were found to be unchanged.

[0036] The formulation according to the invention should have a pH ofbetween 8 and 10, preferably between 8.5 and 9, more preferably a pHbetween 8.7 and 8.9, and particularly 8.8.

[0037] The formulation according to the invention is suitable fortreating pain, inflammation, fever, acute mastitis, diarrhea, lameness,problems with the locomotor apparatus, and respiratory complaints inanimals, preferably acute mastitis, diarrhea, lameness, problems withthe locomotor apparatus and respiratory complaints, especially acutemastitis, diarrhea, lameness, problems with the locomotor apparatus andrespiratory complaints, and most preferably respiratory complaints. Thetreatment may be given in conjunction with antibiotic therapy.

[0038] The formulation according to the invention is suitable fortreating animals, preferably farm animals, and more particularly largefarm animals.

[0039] The formulation according to the invention is suitable fortreating animals, preferably animals up to 500 kg, particularly largeanimals up to 750 kg.

[0040] The dosage of the formulation according to the invention shouldcorresponding to 0.2 to 1.0 mg of active substance per kg of bodyweight,preferably 0.4 to 0.8 mg/kg of bodyweight, more preferably 0.5 to 0.7mg/kg of bodyweight, and particularly preferably 0.6 mg/kg ofbodyweight.

[0041] The formulation according to the invention may be prepared usingthe methods of preparing aqueous liquid formulations known from theliterature. For example, the appropriate excipients may be added to ameloxicam salt solution.

[0042] Various commercial materials for aqueous liquid formulationswhich will allow sealing under inert gas and final sterilization byautoclaving in the finished container may be used as a packagingmaterial for the formulation according to the invention. Such materialsinclude for example ampoules or glass vials, particularly glass vials,e.g., 50 mL or 100 mL glass vials of glass Type I (according to Pharm.Eur/USP) in conjunction with rubber stoppers made ofethylenepropylenenorbornene terpolymer (Type WI 640 grey) and aluminiumcaps.

[0043] The meloxicam solutions according to the invention will now beillustrated by the Examples which follow. Anyone skilled in the art willbe aware that the Examples serve only as an illustration and are not tobe regarded as restrictive.

EXAMPLES

[0044] Example 1: 2% Meloxicam Solution Component Amount (g/L) Meloxicam20.0 Meglumine 14.0 Macrogol 300¹ 150.0 Poloxamer 188² 50.0 Ethanol150.0 Glycine 5.0 EDTA-Na 1.0 1M HCl q.s. ad pH 8.8 1M NaOH q.s. ad pH8.8 Water for injections ad 1000 mL

[0045] Method

[0046] 20 g of meloxicam are dissolved in 500 mL of an aqueous megluminesolution (14g/500 mL) at 90° C. The other excipients are added one afteranother to the solution according to the recipe given above. A pH of 8.8is then achieved using 1M hydrochloric acid and 1M sodium hydroxidesolution. Water is added to the solution until a volume of 1 liter isobtained. Example 2: 2% Meloxicam Solution Component Amount (g/L)Meloxicam 20.0 Meglumine 12.5 PEG 400 100.0 Poloxamer 50.0 Ethanol 150.0Glycine 5.0 EDTA-Na 1.0 1M HCl q.s. ad pH 8.8 1M NaOH q.s. ad pH 8.8Water for injections ad 1000 mL

[0047] Method

[0048] 20 g of meloxicam are dissolved in 500 mL of an aqueous megluminesolution (12.5 g/500 mL) at 90° C. The other excipients are added oneafter another to the solution according to the recipe given above. A pHof 8.8 is then achieved using 1M hydrochloric acid or 1M sodiumhydroxide solution. Water is added to the solution until a volume of 1liter is obtained. Example 3: 2.5% Meloxicam Solution Component Amount(g/L) Meloxicam 25.0 Meglumine 17.5 PEG 300 150.0 Poloxamer 50.0 Ethanol150.0 Glycine 5.0 EDTA-Na 1.0 1M HCl q.s. ad pH 8.8 1M NaOH q.s. ad pH8.8 Water for injections ad 1000 mL

[0049] Method

[0050] 25 g of meloxicam are dissolved in 500 mL of an aqueous megluminesolution (17.5 g/500 mL) at 90° C. The other excipients are added oneafter another to the solution according to the recipe given above. A pHof 8.8 is then achieved using 1M hydrochloric acid or 1M sodiumhydroxide solution. Water is added to the solution until a volume of 1liter is obtained. Example 4: 1.5% Meloxicam Solution Component Amount(g/L) Meloxicam 15.0 Meglumine 10.5 PEG 300 100.0 Poloxamer 50.0 Ethanol150.0 Glycine 5.0 EDTA-Na 1.0 1M HCl q.s. ad pH 8.8 1M NaOH q.s. ad pH8.8 Water for injections ad 1000 mL

[0051] Method 15 g of meloxicam are dissolved in 500 mL of an aqueousmeglumine solution (10.5 g/500 mL) at 90° C. The other excipients areadded one after another to the solution according to the recipe givenabove. A pH of 8.8 is then achieved using 1M hydrochloric acid or 1Msodium hydroxide solution. Water is added to the solution until a volumeof 1 liter is obtained. Example 5: 2% Meloxicam Solution ComponentAmount (g/L) Meloxicam 20.0 Meglumine 14.0 PEG 300 150.0 Poloxamer 50.0p-Chloro-m-cresol 2.0 Glycine 5.0 EDTA-Na 1.0 1M HCl q.s. ad pH 8.8 1MNaOH q.s. ad pH 8.8 Water for injections ad 1000 mL

[0052] Method 20 g of meloxicam are dissolved in 500 mL of an aqueousmeglumine solution (14 g/500 mL) at 90° C. The other excipients areadded one after another to the solution according to the recipe givenabove. A pH of 8.8 is then achieved using 1M hydrochloric acid or 1Msodium hydroxide solution. Water is added to the solution until a volumeof 1 liter is obtained.

What is claimed is:
 1. An aqueous cyclodextrin-free solution ofmeloxicam for administration by oral or parenteral route, comprising apharmacologically acceptable meloxicam salt of an organic or inorganicbase and one or more suitable excipients, wherein the concentration ofdissolved meloxicam salt is more than 10 mg/mL.
 2. The aqueous solutionaccording to claim 1, wherein the meloxicam salt is the sodium ormeglumine salt.
 3. The aqueous solution according to claim 2, whereinthe solution contains meglumine and meloxicam in a molar ratio ofbetween 9:8 and 12:8.
 4. The aqueous solution according to claim 3,wherein the solution contains meglumine and meloxicam in a molar ratioof 10:8.
 5. The aqueous solution according to one of claims 1 to 4,wherein the one or more suitable excipients is selected from the groupconsisting a buffer and a preservative.
 6. The aqueous solutionaccording to claim 5, wherein the preservative is selected from thegroup consisting of ethanol; benzoic acid and the sodium and potassiumsalts thereof; sorbic acid and the sodium and potassium salts thereof,chlorobutanol; benzyl alcohol; phenylethanol; the methyl, ethyl, propyl,and butyl p-hydroxybenzoates; phenol; m-cresol; p-chloro-m-cresol;phenylmercury nitrate; and benzalkonium chloride.
 7. The aqueoussolution according to claim 5, wherein the buffer is selected from thegroup consisting of: glycine; a mixture of glycine and HCl; a mixture ofglycine and sodium hydroxide solution, and the sodium and potassiumsalts thereof; a mixture of potassium hydrogen phthalate andhydrochloric acid; a mixture of potassium hydrogen phthalate and sodiumhydroxide solution; and a mixture of glutamic acid and glutamate.
 8. Theaqueous solution according to one of claims 1 to 4, wherein the one ormore suitable excipients includes a solubilizer.
 9. The aqueous solutionaccording to claim 8, wherein the solubilizer is selected from the groupconsisting of: polyethyleneglycols, polyoxyethylene-polyoxypropylenecopolymers, glycofurol, arginine, lysine, castor oil, propyleneglycol,solketal, polysorbate, glycerol, sorbitol, mannitol, xylitol,polyvinylpyrrolidone, lecithin, cholesterol, 12-hydroxystearicacid-PEG660-ester, propyleneglycol monostearate, polyoxy-40-hydrogenatedcastor oil, polyoxyl-10-oleyl-ether, polyoxyl-20-cetostearylether,polyoxyl-40-stearate, and mixtures thereof.
 10. The aqueous solutionaccording to one of claims 1 to 4, wherein the one or more suitableexcipients is selected from the group consisting of: citric acid,lecithin, gluconic acid, tartaric acid, phosphoric acid, and EDTA andthe alkali metal salts thereof.
 11. The aqueous solution according toone of claims 1 to 4, wherein the shelf-life of the solution afteropening is 28 days or more at ambient temperature.
 12. The aqueoussolution according to claim 5, wherein the shelf-life of the solutionafter opening is 28 days or more at ambient temperature.
 13. The aqueoussolution according to claim 6, wherein the shelf-life of the solutionafter opening is 28 days or more at ambient temperature.
 14. The aqueoussolution according to claim 7, wherein the shelf-life of the solutionafter opening is 28 days or more at ambient temperature.
 15. The aqueoussolution according to claim 8, wherein the shelf-life of the solutionafter opening is 28 days or more at ambient temperature.
 16. The aqueoussolution according to claim 9, wherein the shelf-life of the solutionafter opening is 28 days or more at ambient temperature.
 17. The aqueoussolution according to claim 10, wherein the shelf-life of the solutionafter opening is 28 days or more at ambient temperature.
 18. The aqueoussolution according to one of claims 1 to 4, wherein the solution has along term shelf-life of 24 months or more at ambient temperature in itsoriginal packaging.
 19. The aqueous solution according to claim 5,wherein the solution has a long term shelf-life of 24 months or more atambient temperature in its original packaging.
 20. The aqueous solutionaccording to claim 6, wherein the solution has a long term shelf-life of24 months or more at ambient temperature in its original packaging. 21.The aqueous solution according to claim 7, wherein the solution has along term shelf-life of 24 months or more at ambient temperature in itsoriginal packaging.
 22. The aqueous solution according to claim 8,wherein the solution has a long term shelf-life of 24 months or more atambient temperature in its original packaging.
 23. The aqueous solutionaccording to claim 9, wherein the solution has a long term shelf-life of24 months or more at ambient temperature in its original packaging. 24.The aqueous solution according to claim 10, wherein the solution has along term shelf-life of 24 months or more at ambient temperature in itsoriginal packaging.
 25. The aqueous solution according to one of claims1 to 4, wherein the solution has a pH of between 8.0 and
 10. 26. Theaqueous solution according to claim 1, comprising meloxicam, meglumine,a polyethyleneglycol, a polyoxyethylene-polyoxypropylene copolymer,ethanol, glycine, disodium EDTA, and optionally sodium hydroxide orhydrochloric acid.
 27. The aqueous solution according to claim 1,consisting essentially of meloxicam, meglumine, a polyethyleneglycol, apolyoxyethylene-polyoxypropylene copolymer, ethanol, glycine, disodiumEDTA, water suitable for injection, and optionally sodium hydroxide orhydrochloric acid.
 28. A method of treating pain, inflammation, fever,acute mastitis, diarrhea, lameness, problems with the locomotorapparatus, or respiratory complaints in a mammal, the method comprisingadministering to a mammal in need of such treatment the aqueous solutionaccording to claim
 1. 29. The method according to claim 28, wherein themethod is used in conjunction with antibiotic therapy.
 30. The methodaccording to claim 28, wherein the solution according to claim 1 isadministered in dosage range of from 0.2 to 1.0 mg of activesubstance/kg of bodyweight of the mammal.
 31. The method according toclaim 30, wherein the solution according to claim 1 is administered indosage range of from 0.4 to 0.8 mg of active substance/kg of bodyweightof the mammal.
 32. The method according to claim 30, wherein thesolution according to claim 1 is administered in dosage range of from0.5 to 0.7 mg of active substance/kg of bodyweight of the mammal.